Earlier this year, I noted that a recent publication provided reassurance on PPI safety. (related blog post: PPIs: Good News on Safety). In the journal issue with the printed version, a detailed editorial provides useful context.
DA Corley. Full Text Link: “Safety and Complications of Long-Term Proton Pump Inhibitor Therapy: Getting Closer to the Truth” Gastroenterol 2019; 157: 604:-7.
The Table 1 contrasts the useful information from this large double-blind randomized study and prior data/data quality.
The new study found NO ASSOCIATION between PPI use and kidney disease, dementia, bone fractures, myocardial infarction, pneumonia, or gastrointestinal malignancies.
Recent publications have summarized both the evidence and evidence-based approaches toward teasing out whether proton pump inhibitors cause certain diseases or are only associated with them through other pathways (e.g., confounding). Helpful strategies include using the classic criteria for evaluating causation such as the:
- strength of the association
- consistency of the findings between studies
- specificity when an outcome happens almost exclusively from a specific exposure
- temporality such that the exposure comes before the outcome
- biological gradient whereby higher exposure doses or longer durations increase risk of the outcome
- biological plausibility for the proposed association
- coherence such as between observed effects and known biology of disease
- experiment such as randomized trials that decrease confounding; and
- analogy to similar exposure–disease associations known to be causal…
This massive undertaking included >17,000 patients from 33 countries who were randomized to pantoprazole versus placebo, followed for a median of approximately 3 years, and evaluated prospectively for potential complications. The study found an increased risk of enteric infections among pantoprazole users, a result found in both the intention-to-treat and “as-treated” analyses, which excluded people who stopped their medications. This association makes sense—stomach acid markedly decreases bacterial load in food, so decreasing stomach acid may increase the risk of enteric bacterial infections. The authors found no increased risk for several of the most feared associations previously reported, such as cardiovascular disease, kidney disease (directly measured using estimated glomerular filtration rate), dementia, pneumonia, fracture, and all-cause mortality.
My take: (borrowed from editorial): The current study would indicate, from the strongest study design available,… that there is an increased risk of gastrointestinal infections and no detectable excess risk for several other potentially important clinical events…Given known problems with overprescribing and overuse, patients and clinicians should maintain appropriate vigilance in prescribing acid suppression only to persons with defined indications and at the lowest effective dose and duration.